PROJECT SUMMARY/ABSTRACT This is an application for a KO1 Award for Nathan Price Ph.D., an associate research scientist at Yale Medical School. His research focuses on identifying novel factors involved in the regulation of cellular bioenergetics and determining how these factors contribute to the development of diseases associated with obesity, aging, and metabolic syndrome. The primary objectives of the proposed research are (1) to determine how loss of miR-33 in AgRP neurons impacts regulation of metabolic homeostasis by the brain, (2) establish the specific mechanisms by which miR-33 mediates these effects, and (3) provide Dr. Price with the experience and skills necessary to establish himself as an independent investigator and pursue his future research goals. Prior work has established miR-33 as an important regulator of lipid metabolism, mitochondrial function, and fatty acid oxidation, and demonstrated the effectiveness of anti-miR-33 therapeutics for the treatment of cardiovascular disease in animal models. However, recent work has demonstrated that whole body loss of miR-33 results in a strong predisposition to the development of obesity and metabolic dysfunction, due to increased food intake. Regulation of feeding behavior by the brain is primarily mediated through AgRP and POMC neurons, which promote signals of hunger and satiety, respectively. The proposed research strategy will utilize a newly developed mouse model that lacks miR-33 in AgRP neurons, which are responsible for promoting feeding behavior. The preliminary data provided indicate that loss of miR-33 in AgRP neurons promotes obesity and metabolic function in a manner similar to whole body miR-33 deficiency. This work will involve an in-depth analysis of the specific impact of miR-33 in AgRP neurons on the regulation of feeding and obesity, and determine the mechanisms by which miR-33 mediates these effects. Utilization of cutting edge techniques for identifying changes in actively translated mRNAs only in AgRP neurons will allow us to identify miR-33 targets that have increased expression in AgRP neurons lacking miR-33. Furthermore, we will be able to assess the likelihood that these genes are involved in mediating the effects of miR-33 on obesity and metabolic function by selectively knocking down specific target genes only in AgRP neurons. This work will provide an improved understanding of the mechanisms by which miR-33 regulates obesity and metabolic function, and offer necessary insight into possible new mechanisms for the treatment of metabolic diseases. The proposed research will also facilitate Dr. Price?s growth as a researcher by providing experience in studying central regulation of metabolism, and promoting the development of new skills that can be utilized in his future research. Dr. Price?s mentors and collaborators will oversee his training in these areas, and provide the expertise and experience necessary to carry out the proposed research. They, along with Dr. Price?s advisory committee, will help guide his career development toward his ultimate goal of becoming an independent academic investigator.